CD95 (FAS) DEPENDENT ELIMINATION OF SELF-REACTIVE B-CELLS UPON INTERACTION WITH CD4(-CELLS() T)

THE recessive mouse mutations lpr and gld create deficiencies in an in teracting pair of cell surface molecules, CD95 (Fas/APO-1) and Fas-lig and (FasL), respectively(1-3), resulting in autoantibody production re sembling human systemic lupus erythematosus(4). The mechanisms of self -tolerance affected by deficiency in either molecule are not establish ed, but CD95 deficiency both in B cells and in CD4(+) T cells recogniz ing major histocompatibility complex (MHC) class II molecules is requi red for autoimmunity in lpr mice(5-8). Here we track the outcome of in vivo interactions between B cells and CD4(+) T cells that recognize a transgene-encoded autoantigen, hen egg lysozyme (HEL), using cells fr om mice transgenic for immunoglobulin and T-cell receptor (TCR) genes. B cells that had not previously encountered HEL autoantigen (naive ce lls) were triggered into proliferation and antibody-production upon in teraction with antigen and HEL-specific CD4(+) T cells. By contrast, B cells that had been chronically exposed to HEL during their developme nt and carried desensitized surface immunoglobulin (sIg) antigen recep tors(9) (anergic cells) did not produce antibody but instead were elim inated in the presence of HEL-specific CD4(+) T cells. CD95-deficient anergic B cells, however, were not eliminated by CD4(+) T cells and we re triggered to proliferate. These findings identify a novel regulator y step for eliminating autoreactive B cells that seems unique in its d ependence on CD95.